Linezolid is the first-in-class drug and was approved in 2000 for a number of clinical applications including the treatment of nosocomial and community-acquired pneumonia and skin infections caused by Staphylococcus aureus/Methicillin-resistant S. aureus, Vancomycin-resistant Enterococci, and Streptococcus pneumoniae (Pen-S). Linezolid exhibits in vitro bacteriostatic activity against Mycobacterium tuberculosis, including multidrug-resistant (MDR) and extensively drug resistant (XDR) strains, with a minimum inhibitory concentration (MIC) of less than 1 μg/ml. However, it has demonstrated only modest activity in murine models of tuberculosis. Nonetheless, Linezolid has been used off-label in combination regimens to treat multidrug-resistant tuberculosis.
Oxazolidinones currently in clinical development show bone marrow toxicity in animals after long term administration (i.e., greater than one month) that is believed to be related to mitochondrial protein synthesis (MPS) inhibition, with very narrow safety margins or no safety margins. Since the antimicrobial mode of action of this class of compounds is inhibition of microbial protein synthesis, the MPS inhibition and consequent bone marrow toxicity exhibited by these compounds is considered mechanism specific. These oxazolidinones generally show high clearance and so require administration of high doses in clinical treatment of TB or the other indications for which they are being developed (e.g., 500 mg to 1600 mg daily) to achieve efficacious exposures. Therefore, it would be highly desirable to identify a new generation of oxazolidinones for TB treatment that would demonstrate improved potency and efficacy against TB, reduced systemic clearance to reduce the daily dose below 500 mg, and diminished MPS inhibition and related bone marrow toxicity, resulting in an improved safety margin for long term administration.